Our proposal addresses the important issue of predicting in a more accurate and patient specific manner the clinical course for early stage CLL and MBL. CLL-Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies, accounting for ~11% of all hematologic neoplasms. CLL remains an incurable and devastating malignancy. In addition to having a life expectancy that is substantially shorter than that of age-matched individuals in the general population, individuals living with CLL must also deal with an increased risk of infections, second cancers, and autoimmune complications that can have profound consequences for their quality of life. However there is extreme heterogeneity in the clinical course of CLL patients best illustrated by the fact that 70% of all CLL patients will ultimately require therapy. This latter outcome is complicated since most newly diagnosed CLL patients present to their physician with very early stage disease. While there have been remarkable advances in our understanding of progression events in CLL, our ability to accurately predict which early stage patient will progress to need for therapy is still crude. MBL-Individuals with high count MBL have a circulating clonal B-cell population, an absolute B-cell count <5x109/L and no other features of a lymphoproliferative disorder. Prevalence studies suggest that 3-5% of the general population over the age of 40 have MBL indicating that MBL may be one of the most common premalignant conditions in humans and that the precursor state is 200 times more common than the disease itself. It is now known that nearly all cases of CLL had pre-existent MBL and that ~1%/year of individuals with MBL progress to symptomatic CLL, providing evidence that MBL is a premalignant state. Individuals with either MBL or early stage CLL have significant anxiety because of the unknown course they make take. The distinction between individuals with higher count MBL and Rai 0 CLL has been arbitrarily defined using a B-cell threshold of 5 x109/L (below this threshold: MBL; above this threshold: Rai 0 CLL). Given this we prefer to define these individuals as patients with small CLL like B-cell clones. We are now poised via this proposal to make dramatic breakthroughs in our ability to more accurately determine which patients with small CLL like B-cell clones (early stage CLL and MBL individuals) will progress and require therapy. This is because of our recent discovery of a novel prognostic model that has a c-statistic of .75 which is currently the most accurate means of predicting risk for progression in CLL. This prognostic index is relatively simple to use as it incorporates routinely available clinical, serum, genetic and molecular markers of the CLL process. It is our quest in this proposal to further enhance the c-statistic of the prognostic inde using key genetic and microenvironmental features so that we can be even more accurate in our ability to counsel and predict the clinical outcome of individuals with small CLL like B-cell clones. In this proposal we work to develop a reliable and accurate way to determine which individuals with small circulating B-cell clones have a clinically significant medical condition an to use this knowledge to develop an enhanced approach to diagnosis, risk stratification, and clinical management.